The inflammatory cytokines, IL-1β and TNF-α play an important role in a number of inflammatory diseases such as rheumatoid arthritis. C. Dinarello et al,. Inflammatory cytokines: lnterleukin-1 and Tumor Necrosis Factor as Effector Molecules in Autoimmune Diseases Curr. Opin. Immunol. 1991, 3, 941–48. Arthritis is an inflammatory disease which affects millions of people and can strike at any joint of the human body. Its symptoms range from mild pain and inflammation in affected joints, to severe and debilitating pain and inflammation. Although the disease is associated mainly with aging adults, it is not restricted to adults. The most common arthritis therapy involves the use of nonsteroidal antiinflammatory drugs (NSAID) to alleviate the symptoms. However, despite their widespread use, many individuals cannot tolerate the doses necessary to treat the disease over a prolonged period of time. In addition, NSAIDs merely treat the symptoms of disease without affecting the underlying cause. Other drugs, such as methotrexate, gold salts, D-pencillamine, and prednisone are often used when patients fail to respond to NSAIDS. These drugs also have significant toxicities and their mechanism of action remain unknown.
Receptor antagonists to IL-1β and monoclonal antibodies to TNF-α have been shown to reduce symptoms of rheumatoid arthritis in small-scale human clinical trials. In addition to protein based therapies, there are small molecule agents which inhibit the production of these cytokines and have demonstrated activity in animal arthritis models. J. C. Boehm et al., 1-Substituted 4-Aryl-5-pyridinylimidazoles: A New Class of Cytokine Suppressive Drugs With Low 5-Lipoxygenase and Cyclooxygenase Inhibitory Potency, J. Med. Chem., 1996, 39, 3929–37. Of these small molecule agents, SB 203580 has proved effective in reducing the production of TNF-α and IL-1 in LPS stimulated human monocyte cell lines with IC50 values of 50 to 100 nM. J. Adams et al., Imidazole Derivatives And Their Use as Cytokine Inhibitor, International Patent application WO 93/14081, Jul. 23, 1993. In addition to this in vitro test, SB 203580 inhibits the production of the inflammatory cytokines in rats and mice at IC50 values of 15 to 25 mg/kg. A. M. Badger, et al, Pharmacological Profile of SB 203580, A Selective Inhibitor of Cytokine Suppressive Binding Protein/p38 Kinase, in Animal Models of Arthritis, Bone Resorption, Endotoxin Shock and Immune Function, The Journal of Pharmacology and Experimental Therapeutics, 1996, 279, 1453–61. Although human data is currently unavailable for SB 203580, monoclonal antibodies to TNF-α have proved efficacious in the treatment of rheumatoid arthritis. M. J. Elliot et al., Treatment of Rheumatoid Arthritis with Chimeric Monoclonal Antibodies to Tumor Necrosis Factor α, Arthritis Rheum. 1993 36, 1681–90. Due to SB 203580's oral activity and potency in animal models, researchers have suggested that a compound with this profile has potential as a viable treatment for rheumatoid arthritis. A. M. Badger, et al. Pharmacological Profile of SB 203580, A Selective Inhibitor of Cytokine Suppressive Binding Protein/p38 Kinase, in Animal Models of Arthritis, Bone Resorption, Endotoxin Shock and Immune Function, The Journal of Pharmacology and Experimental Therapeutics, 1996, 279, 1453–61.
SB 203580 and other small molecule agents reduce the production of inflammatory cytokines by inhibiting the activity of a serine/threonin kinase p38 (note other researchers refer to this enzyme as CSBP), at an IC50 of 200 nM. D. Griswold et al., Pharmacology of Cytokine Suppressive Anti-inflammatory Drug Binding Protein (CSPB), A Novel Stress-induced Kinase, Pharmacology Communications, 1996, 7, 323–29. Although the precise mechanism of this kinase is unknown, it has been implicated in both the production of TNF-α and the signaling responses associated with the TNF-α receptor.

U.S. Pat. No. 5,965,583 (hereby incorporated by reference) describes substituted imidazoles of the formula:
wherein R1 is phenyl, substituted phenyl (where the substituents are selected from the group consisting of C1-5alkyl, halogen, nitro, trifluoromethyl and nitrile), or heteroaryl where the heteroaryl contains 5 to 6 ring atoms; R2 is phenyl, substituted phenyl (where the substituents are selected from the group consisting of C1-5alkyl, halogen, nitro, trifluoromethyl and nitrile), heteroaryl where the heteroaryl contains 5 to 6 ring atoms and is optionally C1-5alkyl substituted; R3 is hydrogen, SEM, C1-5alkoxycarbonyl, aryloxycarbonyl, arylC1-5alkyloxycarbonyl, arylC1-5alkyl, substituted arylC1-5alkyl (where the aryl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, C1-5alkoxy, halogen, amino, C1-5alkylamino, and diC1-5alkylamino), phthalimidoC1-5alkyl, aminoC1-5alkyl, diaminoC1-5alkyl, succinimidoC1-5alkyl, C1-5alkylcarbonyl, arylcarbonyl, C1-5alkylcarbonylC1-5alkyl, aryloxycarbonylC1-5alkyl, heteroarylC1-5alkyl where the heteroaryl contains 5 to 6 ring atoms; R4 is —A—(CH2)q—X wherein A is vinylene, ethynylene or
where R5 is selected from the group consisting of hydrogen, C1-5alkyl, phenyl and phenylC1-5alkyl; q is 0–9; X is selected from the group consisting of hydrogen, hydroxy, vinyl, substituted vinyl (where one or more substituents are selected from the group consisting of fluorine, bromine, chlorine and iodine), ethynyl, substituted ethynyl (where the substituents are selected from one or more members of the group consisting of fluorine, bromine, chlorine and iodine), C1-5alkyl, substituted C1-5alkyl (where the alkyl substituents are selected from the group consisting of one or more C1-5alkoxy, trihaloalkyl, phthalimido and amino), C3-7cycloalkyl, C1-5alkoxy, substituted C1-5alkoxy (where the alkyl substituents are selected from the group consisting of phthalimido and amino), phthalimidooxy, phenoxy, substituted phenoxy (where the phenyl substituents are selected from the group consisting of C1-5alkyl, halogen and C1-5alkoxy), phenyl, substituted phenyl (where the phenyl substituents are selected from the group consisting of C1-5alkyl, halogen and C1-5alkoxy), arylC1-5alkyl, substituted arylC1-5alkyl (where the aryl substituents are selected from the group consisting of C1-5alkyl, halogen and C1-5alkoxy), amino, C1-5alkylamino, diC1-5alkylamino, nitrile, oxime, benzyloxyimino, C1-5alkyloxyimino, phthalimido, succinimido, C1-5alkylcarbonyloxy, phenylcarbonyloxy, substituted phenylcarbonyloxy (where the phenyl substituents are selected from the group consisting of C1-5alkyl, halogen and C1-5alkoxy), phenylC1-5alkylcarbonyloxy (where the phenyl substituents are selected from the group consisting of C1-5alkyl, halogen and C1-5alkoxy), aminocarbonyloxy, C1-5alkylaminocarbonyloxy, diC1-5alkylaminocarbonyloxy, C1-5alkoxycarbonyloxy, substituted C1-5alkoxycarbonyloxy (where the alkyl substituents are selected from the group consisting of methyl, ethyl, isopropyl and hexyl), phenoxycarbonyloxy, substituted phenoxycarbonyloxy (where the phenyl substituents are selected from the group consisting of C1-5alkyl, C1-5alkoxy and halogen), C1-5alkylthio, substituted C1-5alkylthio (where the alkyl substituents are selected from the group consisting of hydroxy and phthalimido), C1-5akylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl (where the phenyl substituents are selected from the group consisting of bromine, fluorine, chlorine, C1-5alkoxy and trifluoromethyl); with the proviso: if A is
q is 0 and X is H, R3 may not be SEM; and pharmaceutically acceptable salts thereof as useful in the treatment of diseases associated with the overproduction of inflammatory cytokines.
U.S. Pat. No. 6,040,320 (hereby incorporated by reference) also describes substituted imidazoles of the formula:
wherein R1 is phenyl, heteroaryl wherein the heteroaryl contains 5 to 6 ring atoms, or substituted phenyl wherein the substituents are independently selected from one or members of the group consisting of C1-5alkyl, halogen, nitro, trifluoromethyl and nitrile; R2 is phenyl, heteroaryl wherein the heteroaryl contains 5 to 6 ring atoms, substituted heteroaryl wherein the substituents are independently selected from one or more members of the group consisting of C1-5alkyl and halogen, or substituted phenyl wherein the substituents are independently selected from one or members of the group consisting of C1-5alkyl, halogen, nitro, trifluoromethyl and nitrile; R3 is hydrogen, SEM, C1-5alkoxycarbonyl, aryloxycarbonyl, arylC1-5alkyloxycarbonyl, arylC1-5alkyl, phthalimidoC1-5alkyl, aminoC1-5alkyl, diaminoC1-5alkyl, succinimidoC1-5alkyl, C1-5alkylcarbonyl, arylcarbonyl, C1-5alkylcarbonylC1-5alkyl, aryloxycarbonylC1-5alkyl, heteroarylC1-5alkyl where the heteroaryl contains 5 to 6 ring atoms, or substituted arylC1-5alkyl wherein the aryl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, C1-5alkoxy, halogen, amino, C1-5alkylamino, and diC1-5alkylamino; R4 is (A)n—(CH2)q—X wherein A is sulfur or carbonyl; n is 0 or 1; q is 0–9; X is selected from the group consisting of hydrogen, hydroxy, halogen, vinyl, ethynyl, C1-5alkyl, C3-7cycloalkyl, C1-5alkoxy, phenoxy, phenyl, arylC1-5alkyl, amino, C1-5alkylamino, nitrile, phthalimido, amido, phenylcarbonyl, C1-5alkylaminocarbonyl, phenylaminocarbonyl, arylC1-5alkylaminocarbonyl, C1-5alkylthio, C1-5alkylsulfonyl, phenylsulfonyl, substituted sulfonamido wherein the sulfonyl substituent is selected from the group consisting of C1-5alkyl, phenyl, arylC1-5alkyl, thienyl, furanyl, and naphthyl; substituted vinyl wherein the substituents are independently selected from one or members of the group consisting of fluorine, bromine, chlorine and iodine, substituted ethynyl wherein the substituents are independently selected from one or more members of the group consisting of fluorine, bromine, chlorine and iodine, substituted C1-5alkyl wherein the substituents are selected from the group consisting of one or more C1-5alkoxy, trihaloalkyl, phthalimido and amino, substituted phenyl wherein the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen and C1-5alkoxy, substituted phenoxy wherein the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen and C1-5alkoxy, substituted C1-5alkoxy wherein the alkyl substituent is selected from the group consisting of phthalimido and amino, substituted arylC1-5alkyl wherein the alkyl substituent is hydroxyl, substituted arylC1-5alkyl wherein the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen and C1-5alkoxy, substituted amido wherein the carbonyl substituent is selected from the group consisting of C1-5alkyl, phenyl, arylC1-5alkyl, thienyl, furanyl, and naphthyl, substituted phenylcarbonyl wherein the phenyl substituents are independently selected from one or members of the group consisting of C1-5alkyl, halogen and C1-5alkoxy, substituted C1-5alkylthio wherein the alkyl substituent is selected from the group consisting of hydroxy and phthalimido, substituted C1-5alkylsulfonyl wherein the alkyl substituent is selected from the group consisting of hydroxy and phthalimido, substituted phenylsulfonyl wherein the phenyl substituents are independently selected from one or members of the group consisting of bromine, fluorine, chlorine, C1-5alkoxy and trifluoromethyl, with the proviso: if A is sulfur and X is other than hydrogen, C1-5alkylaminocarbonyl, phenylaminocarbonyl, arylC1-5alkylaminocarbonyl, C1-5alkylsulfonyl or phenylsulfonyl, then q must be equal to or greater than 1; if A is sulfur and q is 1, then X cannot be C1-2alkyl; if A is carbonyl and q is 0, then X cannot be vinyl, ethynyl, C1-5alkylaminocarbonyl, phenylaminocarbonyl, arylC1-5alkylaminocarbonyl, C1-5alkylsulfonyl or phenylsulfonyl; if A is carbonyl, q is 0 and X is H, then R3 is not SEM; if n is 0 and q is 0, then X cannot be hydrogen; and pharmaceutically acceptable salts thereof as useful in the treatment of diseases associated with the overproduction of inflammatory cytokines.
The object of the present invention is to provide a series of substituted imidazoles, pharmaceutical compositions containing them and intermediates used in their manufacture. Another object is to provide a method for treating diseases associated with the overproduction of inflammatory cytokines.